Presence of high-endothelial venules correlates with a favorable immune microenvironment in oral squamous cell carcinoma

Abstract

Oral squamous cell carcinomas are associated with a poor prognosis, which may be partly due to functional impairment of the immune response. Lymphocyte recruitment to the tumor site is facilitated by high-endothelial venules, whereas expression of programmed-death ligand 1 (PD-L1) can impair T-cell function. Thus, we hypothesize that these factors are important in shaping the immune response in oral squamous cell carcinoma. In the present study, we characterized the immune infiltrate in formalin-fixed, paraffin-embedded tumor samples from 75 oral squamous cell carcinoma patients. We used immunohistochemistry to determine the distribution of immune cell subsets, high-endothelial venules, and PD-L1, as well as quantitative real-time polymerase chain reaction to assess the expression of inflammatory cytokines and chemokines associated with lymphocyte trafficking. Finally, we calculated correlations between the presence of immune cell subsets, the gene expression patterns, high-endothelial venules, PD-L1, and the clinicopathological parameters, including patient survival. The presence of high-endothelial venules correlated with increased number of CD3+ T cells and CD20+ B cells, higher levels of the chemokines CXCL12 and CCL21, and lower levels of CCL20, irrespective of the tumors' T stage. In univariate analysis, high levels of CD20+ B cells and CD68+ macrophages, positive high-endothelial venule status, and low T and N stages predicted longer patient survival. However, only the presence of high-endothelial venules and a low T stage were independent positive prognosticators. This indicates that high-endothelial venules are important mediators and a convenient marker of an antitumor immune response in oral squamous cell carcinoma. Our findings suggest that these vessels are a potential immunomodulatory target in this type of cancer. PD-L1 staining in tumor cells correlated with lower T stage, increased infiltration of CD4+ cells, and higher expression of several inflammation-related cytokines. Thus, oral squamous cell carcinomas rich in CD4+ cells may preferentially respond to PD-1/PD-L1 blockade therapy.

Tissue-infiltrating immune cells as prognostic markers in oral squamous cell carcinoma: a systematic review and meta-analysis

“…Macrophages were the most commonly studied cells of those addressed in this review [27][28][29][30][31][32][33][34][35][36][37][38][39][40][41] (Table 1), and the majority of the studies reported a negative effect on survival of this cell type. A few studies scored macrophages infiltrating the tumour islands and the tumour-stroma separately and found that the effect on survival differed between the compartments.…”

“…Thirteen different studies assessed various subsets of T cells 23,28,29,34,40,[44][45][46][47][48][49][50][51] (Table 3). High numbers of tumourinfiltrating CD3+ T cells (pan T cell marker), CD4+ T cells (T helper (Th) cell marker) or CD8+ T cells (T cytotoxic (Tcyt) marker) were usually associated with somewhat longer survival, whereas high numbers of forkhead box P3 (FOXP3)+ T-regulatory cells showed significant association with decreased survival in two of the five studies addressing this cell type.…”

“…We could not perform meta-analysis for the other T cell types due to lack of data. B cells were analysed in five studies using four different markers 23,28,34,49,52 (Table 3). B cells recognised by the pan B-cell markers CD19 and CD20 were mostly associated with survival benefits, although statistically significant in only two of the four studies.…”

“…Seven different articles assessed the prognostic value of DC, using seven different markers 28,45,[53][54][55][56][57] (Table 2). High numbers of both immature CD209+ DC and plasmacytoid CD123+ DC were associated with decreased survival in one study, whereas high numbers of the other subsets of DC were mostly associated with improved survival.…”

Fully Human Antibodies for Malignant Pleural Mesothelioma Targeting

“…TLS density is associated with higher numbers of CD8+ and CD4+ T-cells in tumors [76], and evidence indicates that TLSs play a major role in controlling tumor invasion and metastasis. A positive impact of TLS density on OS and disease-free survival in lung cancer [71,[76][77][78], colorectal cancer [79,80], pancreatic cancer [81,82], oral squamous cell carcinoma [83], and invasive breast cancer [70,[84][85][86] has been documented. Importantly, its prognostic value is independent of tumor-node-metastasis (TNM) staging in most malignancies, suggesting TLS can induce a systemic, long-lasting anti-tumor response.…”